DID - Nov. 24, 2009 Issue

FDA to Accept Supplier Test Data, Statements on Residual Solvents

The FDA’s final guidance on residual solvents differs from the draft version by permitting manufacturers to submit test data or statements on
the solvents from qualified suppliers of drug components.

The suppliers’ reports of analysis must show the components comply with the U.S. Pharmacopeia (USP) General Chapter <467> requirement for
control of residual solvents, according to the guidance to be published in the Nov. 25 Federal Register. If the test limits are met for the drug
product components, finished product testing is unnecessary, it says.

The guidance, intended to help manufacturers comply with the USP requirement, tells manufacturers with NDAs and ANDAs for noncompendial drug products
to refer to International Conference on Harmonisation (ICH) “Guidance for Industry Q3C Impurities: Residual Solvents” for recommendations on
solvent classification and permitted daily exposure.

That guidance’s companion document lists several solvents, broken down into risk classes, and advises manufacturers on appropriate levels to use
for each one if they must be included in drug products.

According to the ICH guidance, known human carcinogens, strongly suspected human carcinogens and environmental hazards should not be used. However,
if their use is unavoidable in order to produce a drug product with a significant therapeutic advance, then their levels should be restricted.

Nongenotoxic animal carcinogens or possible causative agents of other irreversible toxicity should be limited in pharmaceutical products, the ICH guidance
says.

Solvents with low toxic potential to humans may be considered less toxic and of lower risk to human health. Amounts of these residual solvents of 50
mg per day or less would be acceptable without justification, it says. Higher amounts may also be acceptable if they are realistic in relation to manufacturing
capability and good manufacturing practice.

Manufacturers using solvents with no adequate toxicological data should justify residual levels of these solvents in pharmaceutical products, the ICH
says.

The levels in the ICH guidance and USP requirement also should be considered for products that are not subject to an NDA or ANDA, such as OTC monograph
products.

The agency revised the final version based on 12 comments from industry, including AstraZeneca, Pfizer and PhRMA. It replaces a 2008 draft version
(DID, Aug.
7, 2008).

Nine Companies Warned by FDA for Distributing Unapproved Drugs

The FDA has sent warning letters to nine distributors of unapproved drugs — at least three of which purchased the products from ANIP Acquisition,
which received a warning letter earlier this year for selling unapproved pharmaceuticals.

The agency sent the similarly worded warning letters to companies distributing unapproved, misbranded and adulterated drugs, which were dated Nov. 13
and posted Tuesday on the FDA website. Each letter refers to a warning letter sent earlier this year to the manufacturer of the products; however, the
manufacturer’s name is redacted in eight of the letters and product names are redacted in all of them.

Cornerstone BioPharma spokesman David Price told DID the drugs referenced in the letter it got were purchased from ANIP and that the FDA enclosed
a warning letter sent to ANIP in August for marketing 30 unapproved products (DID,
Sept. 10). He said the company no longer sells the products mentioned in the letter — antihistamines Deconsal CT (phenylephrine HCl/pyrilamine
maleate) chewable tablets and Deconsal DM (phenylephrine/pyrilamine maleate/dextromethorphan hydrobromide) chewable tablets.

Another letter, to Accentia Biopharmaceuticals, notes the August warning letter to ANIP for manufacturing unapproved drugs and does not redact the company
name. Accentia spokesman Doug Calder told DID the company no longer sells the product mentioned in its letter, Respi-TANN (carbetapentane/pseudoephedrine)
tannate antihistamine suspension, and has been told by the FDA that the agency will update its website to show the matter is closed.

Tiber Laboratories also has discontinued distributing affected products after learning about the August warning letter to ANIP, its manufacturer for
the products, spokesman Rick Henson told DID.

Although the warning letters to each company reference the manufacturer, they add, “You are responsible for investigating determining the causes
of the violations … and for preventing their recurrence.”

The warning letters were sent to:

Accentia Biopharmaceuticals;

Allegis Pharmaceuticals;

Cornerstone BioPharma;

Everett Laboratories;

Larken Laboratories;

Tiber Laboratories;

Victory Pharma;

WraSer Pharmaceuticals; and

Zyber Pharmaceuticals.

ANIP and the remaining recipients of the letters did not respond to requests for comment by press time, or could not be reached at the phone numbers
listed on the letters.

FDA Amends Labeling Requirements for IAAA Warnings

Manufacturers of OTC acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) do not have to put a warning about acetaminophen’s risk of
liver injury and NSAID-related stomach bleeding on each blister unit of a blister card, according to an amended final rule.

In an amendment that revises three requirements in its final rule on the products’ labeling, the FDA tells drugmakers that they only need to put
the appropriate warning on the blister card if the warning remains intact and readable when the drug is removed from the card (DID,
April 29).

The amendments to the OTC internal analgesic, anti-pyretic and anti-rheumatic (IAAA) drug labeling rule take effect April 29, 2010, for all products,
including those with annual sales of less than $25,000, the FDA says.

The other two requirements involve a “see new warnings” flag on the principal display panel (PDP) of the products’ retail packaging
and the wording of the first bulleted statement in the liver injury warning, according to the rule.

The flag must be added to the PDP by April 29, 2010, and remain there for at least one year.

The FDA is modifying the wording of the liver injury warning that manufacturers must add to all OTC drug products containing acetaminophen. It will
allow an optional statement at the end of the first bulleted statement in the warning, saying “more than [insert maximum number of daily dosage units]
in 24 hours, which is the maximum daily amount [optional: for this product].”

The agency made this modification so manufacturers of acetaminophen products containing multiple active ingredients can communicate to patients that
the maximum daily dosage may be limited by an ingredient other than acetaminophen.

Court Sides With Merck in Second Case Over Fosamax

A federal court has dismissed allegations that Merck’s osteoporosis drug Fosamax causes jaw bone destruction, two months after declaring a mistrial
in a similar suit involving Fosamax liability.

In granting summary judgment, Judge John Keenan of the U.S. District Court for the Southern District of New York said an expert witness for plaintiff
Bessie Flemings was unqualified and that Flemings failed to otherwise prove her case, according to the opinion. He called the lawsuit “the second
of three bellwether trials in a multi-district products liability litigation concerning the osteoporosis drug Fosamax.”

Flemings was seeking damages for alleged jaw and dental problems she experienced after taking Fosamax (alendronate sodium). The drug’s labeling
notes that osteonecrosis of the jaw (ONJ), typically associated with tooth extraction or local infection, has been reported in patients taking bisphosphonates
such as Fosamax.

Flemings and her family physician, Walter Rose, claimed she developed ONJ in 2006 after taking the product for severe osteoporosis, according to the
District Court opinion. But the judge says that Rose’s opinion is derived from a “subjective belief” rather than from scientific knowledge
and that he is not qualified as an expert under Rule 702 and his opinion is inadmissible.

Specifically, the judge said Rose did not explain whether his theory that Flemings’ ONJ would heal when she stopped taking Fosamax had been tested,
peer reviewed and published, and whether it was generally accepted in the scientific community.

Flemings also offered no evidence to support her claim, Paul Strain, outside counsel for Merck, says in a statement. “Unfortunately, Ms. Flemings
had medical problems that cause people to develop jaw problems regardless of whether they were taking Fosamax,” he adds.

The first bellwether lawsuit to go to trial ended in to a mistrial in September after the jury failed to reach a verdict. That case, Boles v. Merck,
also alleged that Fosamax caused deterioration of the plaintiff’s jaw (DID,
Sept. 14). The second case was Flemings v. Merck & Co., Inc., for which the In re: Fosamax Products Liability Litigation opinion
was filed Nov. 23.

The third bellwether case, Maley v. Merck, is set to go to trial April 12, 2010, according to a recent statement by Merck. As of Sept. 30,
about 953 Fosamax liability cases had been filed by an estimated 1,334 plaintiff groups in state or federal courts, according to the statement. — Meg
Bryant

Shire Submits European MAA for Type 1 Gaucher’s Disease Treatment

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to speed its review of Shire’s marketing
authorization application (MAA) for velaglucerase alfa, an enzyme replacement therapy for the treatment of Type 1 Gaucher’s disease, in hopes of
ending the current shortage of Gaucher’s treatments.

The review is scheduled to begin in CHMP’s December cycle, Shire says in a statement Tuesday. The company previously filed applications for velaglucerase
alfa in the U.S. and Canada. The FDA has set an action date of Feb. 28 for the company’s NDA, Shire spokeswoman Jessica Cotrone told DID Tuesday.

The discovery last summer of viral contamination at Genzyme’s Allston, Mass., plant led to the disposal of 80 percent of Cerezyme (imiglucerase)
material and sparked a worldwide shortage of the only approved treatment for patients with Gaucher’s disease, a rare inherited disorder. Genzyme
has since reopened the facility and plans to begin meeting demand for the drug in the first quarter of 2010 (DID,
Sept. 24).

In the wake of the shortage, the FDA asked Shire and Protalix Biotherapeutics to speed Gaucher’s treatment applications (DID,
July 7). In August, the agency approved Protalix’s test protocol for prGCD, its experimental treatment for Gaucher’s disease, and
the company hopes to file an NDA by year’s end (DID, July
15).

Velaglucerase alfa is derived from human cell line technology. The drug has been studied in more than 100 patients at 24 sites in 10 countries, the
company says in a Sept. 1 statement. Results from three clinical trials met all primary and secondary endpoints, Shire says. In one study,
previously untreated patients with Gaucher’s disease, patients given a 60 U/kg IV dose of velaglucerase alfa every other week for 12 weeks showed
a statistically significant increase in mean hemoglobin concentration compared with baseline. Patients’ hemoglobin, platelet count and spleen volume
also improved at the 45 U/kg IV dose.

Patients in Europe and elsewhere outside the U.S. can get velaglucerase alfa through preapproval access programs developed by Genzyme and regulatory
authorities to address the ongoing supply shortage. U.S. patients can get the drug under a treatment IND that began in September.

Genzyme’s Cerezyme had $1.2 billion in global sales last year, according to the company’s financial report. — Meg Bryant